Certain substituted 2-mercaptoimidazole derivatives



United States Patent 3,505,350 CERTAIN SUBSTITUTED Z-MERCAPTO- IMIDAZOLEDERIVATIVES Karl J. Doebel, Ossining, N.Y., and Andr R. Gagneux,

Basel, Switzerland, assignors to Geigy Chemical Corporation, Greenburgh,N.Y., a corporation of New York No Drawing. Continuation-impart ofapplication Ser. No. 500,245, Oct. 21, 1965. This application Apr. 17,1968, Ser. No. 721,930

Int. Cl. C07d 49/34, 49/36 US. Cl. 260309 6 Claims ABSTRACT OF THEDISCLOSURE The compounds are of the class of substituted2-mercaptoimidazole derivatives which have anti-inflammatory utility.Illustrative examples are 1- (4-fluorophenyl)-5- methyl 2mercaptoimidazole and 1 methyl 5 phenyl-2-mercaptoimidazole.

Cross-reference to related cases This application is acontinuation-in-part of application, Ser. No. 500,245, filed Oct. 21,1965, now abandoned, which is a continuation-in-part of application,Ser. No. 204,643, filed June 22, 1962, now abandoned.

Detailed disclosure This invention relates to certain derivatives of2-mercaptoimidazole which possess valuable pharmaceutical properties.

More specifically, the compounds of this invention are substituted2-mercaptoimidazole derivatives which can be represented by thefollowing structural formula:

wherein:

The term lower alkyl as used herein per se or as included in the termlower alkoxy means saturated monovalent aliphatic radicals of theformula -C H wherein m designates an integer of less than 5 and isinclusive of both straight chain and branched chain radicals except thatthe integer is less than 4 in carbon-lower-alkoxy, the term loweralkvlene as used herein means un- "ice saturated monovalent aliphaticradicals of the general formula C H wherein n designates an integer ofless than 5 and is inclusive of both straight chain and branched chainradicals and the term monocarbocyclic aryl as used herein means phenyland phenyl mono-, dior tri-substituted by lower alkyl, lower alkoxy,halogen (fluorine, bromine, chlorine, iodine) or trifluoromethyl.

The compounds defined by the above formula can be synthesized, forexample, by reacting a suitable primary amine, formaldehyde and ana-isonitrosoketone. The reaction mixture is then treated with a reagentwhich yields the hydrosulfide ion, metal sulfides, preferably sodiumsultide, potassium sulfide, calcium sulfide, etc; ammonium sulfide andother equivalents. The compounds obtained may be further modified byhydrolysis and decarboxylation. Other modes of preparation of thecompounds of this invention are illustrated in the examples given below.

The present invention comprehends not only the above describedderivatives of Z-mercaptoimidazole in its free base form, but it alsoincludes pharmaceutically acceptable non-toxic acid addition salts whichmay be formed from said compounds in those cases where, e.g. R or R arebasic amino substituents in accordance with conventional practice, byusing appropriate inorganic and organic acids, such as hydrohalic acids,especially hydrochloric and hydrobromic acids, sulfuric, ethanesulfonicand phosphoric acids as well as acetic, aminoacetic, lactic, succinic,malic, econitic, phthalic, tartaric acids, etc.

The methods for the preparation of these compounds can be exemplifiedmore fully by the following illustrative examples. The temperaturestherein are given in degrees centigrade.

EXAMPLE 1 1- (p-methoxyphenyl -5-methyl-2-mercaptoimidazole (a) 1 (pmethoxyphenyl) 2 mercapto 4 carbethoxy-S-methylimidazole.A 37% aqueousformaldehyde solution (10.0 ml.) and 12.32 g. of p-anisidine were mixedin 30 ml. of ethanol. After three minutes a heavy precipitate hadformed. Ethyl isonitrosoacetoacetate (15.9 g. (45%) of material; M.P.203-205". brisk stream of hydrogen sulfide was bubbled through for onehour. The reaction was then stopped and cooled to 5. Recrystallizationof the resulting precipitate from ethanol and then fromchloroform/pentane afforded 13.0 g. (45%) of material; M.P. 203205Analysis.Calcd for C H N O S (M.W. 292.35) (percent): C, 57.50; H, 5.52;N, 9.59; S, 10.97. Found (percent): C, 57.72; H, 5.52; N, 9.80; S,11.22. U.V. (ethanol and HCl): A max: 225 m 6, 17,000; M max: 273 mu; e,14,000; I.R. (CHC13); v C=O) 1720 (b) 1 (p methoxyphenyl) 2 mercapto 4carboxy-5-methylimidazole.-1 (p methoxyphenyl) 2- mercapto-4carbethoxy-5-methylimidazole (27.8 g.) was refluxed with 500 ml. of 3 Nsodium hydroxide for 1 hour; then cooled, filtered and the filtrateacidified and the precipitated acid collected on a Buchner funnel.Recrystallized from dioxane, the desired compound was obtained in ayield of 97%; M.P. 265 (dec.).

Analysis.Calcd for C H N O S (M.W. 264.23) (percent): C, 54.54; H, 4.58;N, 10.60; S. 12.12. Found (percent): C, 54.67; H, 4.78; N, 10.37; S,11.79. U.V. (methanol) x max: 233 m e, 14,000; max: 271 mu; 6. 14,400.

(c) Desired compound.2mercapto-l-(p-methoxyphenyl)4-carboxy-5-methylimidazole (10.7 g., 40mM.) was heated under nitrogen to 280 with magnetic stirring. After fiveminutes the CO -evolution subsided, heating was continued for anotherfive minutes and 50 ml. of ethanol was carefully added once the residuehad solidified. Recrystallization of the reddish mixture from hotethanol gave 6.2 g. (65%) of the desired compound, M.P. 224, 227.

Analysis.-Calcd for C H ON S (M.W. 220.22) (percent): C, 59.99; H, 5.49;N, 12.72; S, 14.54. Found (percent): C, 59.77; H, 5.58; N, 12.54; S,14.54. Uultraviolet spectrum:

max

MeOH 2230 A. $24,000

2670 A. (e=l5,000) HC12230 A. 21,000 2670 A. (e=14,000) NaOH 2230 A.(e=22,000)

EXAMPLE 2 1- (4-methoxyphenyl )-2-rnethylmerc apto-S- methylimidazolehydrochloride 1-(4-methoxyphenyl)-2-mercapto methylimidazole (4.4 g.,0.02 mole) was suspended in water (20 ml.) and 3 N NaOH (6.6 ml.); themixture Was heated to 100 and dimethyl sulfate (0.04 mole, 5.66 ml.) wasadded. Sufiicient dilute NaOH solution was added to maintain reactionmixture just basic to bromcresol purple indicator while heating at 100for one-half hour. The reaction mixture was cooled, neutralized to pH 89with saturated sodium carbonate solution and extracted with chloroform(5 100 ml). The chloroform extract was washed with water, dried oversodium sulfate and evaporated to dryness. The resulting oil (4.4 g.) wasdissolved in isopropanol-isopropyl ether (1:1, 15 ml.) and ethanolic HCl(10 N, 2.5 ml.) was added. The desired product crystallized (1.4 g.,M.P. 210211). The crude product from several reactions (4.0 g.) wasrecrystallized from isopropanol (30 ml.) to yield screening sample 3.5g., M.P. 211-213 (dec.).

Analysis.Calcd for C H C1N OS (M.W. 270.79) (percent): C, 53.22; H,5.58; N, 10.35; S, 11.84; Cl, 13.09. Found (percent): C, 53.00; H, 5.48;N, 10.39; S, 11.90; Cl, 13.36. Ultraviolet spectrum:

x3533 225 m 255 m0 EXAMPLE 3 l,5-dimethyl-Z-mercaptoimidazole Thiscompound was prepared according to the procedure in Burtles et al., J.Chem. Soc. 127, 581 (1925). The compound was recrystallized from ethanol(charcoal treatment) instead of water.

Analysis.-Calcd for C H N S (M.W. 128.2) (percent): C, 46.84; H, 6.29;N, 21.85; S, 25.05. Found (percent): C, 46.86; H, 6.85; N, 21.80; S,24.76.

EXAMPLE 4 1- (n-butyl) -5-1nethyl-2-mercaptoimidazole (a) N-(n-butyl) N[l-(2-hydroxypropyl)]thiourea. A solution of butyl isothiocyanate (5.75g., 0.05 mole) in dry benzene (12 ml.) was added dropwise to a solutionof l-amino-Z-propanol (3.75 g., 0.05 mole) in anhydrous benzene (12 ml.)while cooling in ice bath. The mixture was stirred at room temperatureovernight. Product (9.25 g., M.P. 88-90") crystallized. Tworecrystallizations from ethyl acetate ml.) yielded screening sample (8.1g., M.P. 89-91).

Analysis.-Calcd for C H N SO (M.W. 190.31) (percent): C, 50.49; N, 9.53;N, 14.72. Found (percent): C, 50.19; N, 9.59 N, 14.77. Ultravioletspectrum:

N 212 I (5, 11 ,200); 242 my (e, 13,600)

(b) Desired compound.A mixture of N-butyl-N'-[1(2-hydroxypropyl)]thiourea (9.5 g., 0.05 mole), anhydrous toluene (250ml.) and anhydrous cyclohexanone (150 ml.) was heated under anhydrousconditions to Aluminum isopropoxide (20.4 g., 0.1 mole) was added withthe aid of toluene (50 ml.) and the reaction mixture was heated at withstirring for two hours. The reaction mixture was cooled in an ice bath;water (25 ml.) and sulfuric acid (10%, 50 ml.) were added carefully. Thereaction mixture was again heated under reflux for one-half hour, cooledto room temperature. Additional water (300 ml.) was added. The toluenelayer was separated and the aqueous mixture was extracted withchloroform (3x500 ml.). The combined toluene-chloroform extract waswashed with water, dried over sodium sulfate and evaporated to dryness,first under vacuum and then under high vacuum at 100. Crystallization ofthe residue from ethyl acetate (20 ml.) gave desired product (5.9 g.,M.P. 142145). Recrystallization from isopropanol (15 ml.) yieldedscreening sample (5.4 g., M.P. 142144). The identical product can beobtained by interaction of l-amino 2,2-ethylenedioxypropane with butylisothiocyanate, followed by acid treatment.

Analysis.-Calcd for C H N S (M.W. 170.28) (percent): C, 56.42; H, 8.29;N, 16.45; S, 18.83. Found (percent): C, 56.38; H, 8.21; N, 16.28; S,18.82.

EXAMPLE 5 1,5 -dimethyl-2- (methylmercapto imidazole hydrochloride Asolution of 1,5-dimethyl-Z-mercaptoimidazole (10.2 g., 0.08 mole) andmethyl iodide (22.7 g., 0.24 mole, 9.9 ml.) in anhydrous methanol (200ml.) was heated under reflux for two hours. The solution wa evaporatedto dryness. The residue was suspended in water (80 ml.) and the pH wasadjusted to 9-10 with saturated sodium carbonate solution. The aqueousmixture was extracted with chloroform (4x200 ml.), the chloroformextract was washed with water, dried over sodium sulfate and evaporatedto dryness to give oil 11 g.). To a solution of the oil in isopropanolwas added 9 N ethanolic HCl 12 ml.) While cooling. The resultingsolution was evaporated to dryness and the residue crystallized fromisopropanolisopropyl ether (3:1, 20 ml.) to give desired compound (12.3g., M.P. 142144). Recrystallization from isopro' panol-isopropyl ether(2:1, 30 ml.) yielded screening sample (11.3 g., M.P. 141-143").

Analysis.-Calcd for C H ClN S (M.W. 178.70) (percent): C, 40.32; H,6.20; N, 15.68; S, 17.94; Cl, 19.84. Found (percent): C, 40.14; H, 6.29;N, 15.42; S, 17.87; Cl, 19.86.

EXAMPLE 6 1- (4-fiuorophenyl -5-methyl-2-mercaptoimidazole (a) Nacetonylphthalimide-N acetonylphthalimide was prepared by a slightmodification of the method of R. E. Lancaster and C. A. Vanderwert. J.Org. Chem. 23, 1208 (1958). A mixture of potassium phthalimide (500 g.),l-chloropropanone (345 ml.) and anhydrous benzene (750 ml.) was stirredunder reflux for 5 hours and then at room temperature overnight. Thissuspension was filtered, the salts were well washed with benzene and thebenzene solution was evaporated to dryness. Recrystallization of thecrude product from isopropanol (125 ml.) gave desired compound (295 g.,M.P. 121123).

(b) 1-phthalimido-2,2-ethylenedioxypropane.A solu tion ofN-acetonylphthalimide g., 0.84 mole), ethylene glycol (78 g., 1.26 mole)and p-toluenesulfonic acid acid (4 g.) in anhydrous benzene (1250 ml.)was heated under reflux with continuous water separation for '8 hours.Recrystallization of the residue from ethyl acetate (ca. 75 m1.) gavedesired product g., M.P. 86-91") which was satisfactory for use in thenext reaction. Re-. crystallization of 5 g. from cyclohexane (30 ml.)gave; analytical sample (4.0 g., M.P. SW93)- 1 amino 2,2ethylenedioxypropane.1-phthalimido-2,2-ethylenedioxypropane (134.4 g.,0.525 mole), hydrazine hydrate (0.785 mole, 30.1 ml.) and water (875ml.) were heated under reflux for 2 hours. The solution was cooled,sodium hydroxide (3 N, 150 ml.) was added and the mixture wascontinuously extracted with methylene chloride overnight. The methylenechloride solution was dried over sodium sulfate, evaporated to drynessand the residue was distilled under reduced pressure to give desiredcompound (34.5 g., B.P. 5656.5/l0 mm. n 1.4426). Redistillation of smallfraction gave analytical sample B.P. 5757.5/10 mm. n 1.4423).

(d) N (4 fluorophenyl) N'-[1-(2,2-ethylenedioxy)- propyl]thiourea.4-fluorophenyl isothiocyanate (4.59 g., 0.03 mole) wasdissolved in ethanol (24 ml.); l-amino- 2,2-ethylenedioxypropane wasadded while cooling and crystallization occurred immediately. Themixture was heated under reflux for one-half hour, cooled, and thecrystalline product (7.2 g., M.P. 125-127) was collected.Recrystallization from isopropanol (30 ml.) gave screening sample (6.5g., M.P. 125-127").

Analysis.Calcd for C H N O SF (M.W. 270.33) (percent): C, 53.31; H,5.59; N, 10.36; S, 11.86. Found (percent): C, 53.40; H, 5.72; N, 10.22;S, 11.90.

Ultraviolet spectrum:

A252 245 my (6, 14,000)

(e) Desired compound.1 amino-2,2-ethylenedioxypropane (3.51 g., 0.03mole) was added to a cooled solution of 4-fluorophenylisothiocyanate(4.59 g., 0.03 mole) in ethanol (24 ml.). The mixture Was stirred underreflux for onehalf hour, cooled. Hydrochloric acid (conc. 2.4 ml.) wasadded and the mixture was again heated under reflux for one hour. Thesuspension was cooled, and the product (5.3 g., M.P. 268273 dec.) wascollected. Recrystallization from methanol-ethanol (2:1, 150 ml., re-

duce volume to 75 ml.) gave screening sample (4.5 g., M.P. 2658 dec.).

Ultraviolet spectrum:

Me0H max.

270 my (a, 10,000)

EXAMPLE 7 1-allyl-5-methyl-2-mercaptoimidazole1-amino-2,2-ethylenedioxypropane (7.02 g., 0.06 mole) was added to acooled solution of allyl isothiocyanate (5.94 g., 0.06 mole) inisopropanol (48 ml.). The mixture was heated under reflux for one-halfhour, then cooled. Hydrochloric acid (conc., 4.8 ml.) was added, and themixture was again heated under reflux for one hour. Product (4.6 g.,M.P. 133135) crystallized on cooling. Recrystallization from isopropanol(25 ml.) gave screening sample (3.8 g., M.P. 132135).

Analysis.-Calcd for C7H10N2S (M.W. 154.24) (percent): C, 54.50; H, 6.54;N, 18.16; S, 20.79. Found (percent): C, 54.49; H, 6.84; N, 18.19; S,20.86.

Ultraviolet spectrum:

max.

EXAMPLE 8 l-butyl-S-methyl-Z- carboethoxyrnercapto -imid azolehydrochloride 6 (2.1 g., M.P. 106 dec.). Recrystallization can also beachieved from isopropanolethyl ether.

Analysis.Calcd for C H N O SCl (M.W. 278.81) (percent): C, 47.38; H,6.87; N, 10.05; S, 11.50; Cl, 12.72. Found (percent): C, 47.01; H, 6.96;N, 10.19; S, 11.59; Cl, 12.52.

Ultraviolet spectrum:

Me0H max.

Ethyl isothiocyanate (4.35 g., 0.05 mole) is dissolved in isopropanol(reagent grade, 40 ml.). 1-amino-2,2-ethylenedioxypropane (5.85 g., 0.05mole) was added and the mixture was heated under reflux for one-halfhour. Hydrochloric acid (conc., 4.0 ml.) was added and the solution wasagain heated under reflux for one hour. Product (5.5 g., M.P. l86188)crystallized on cooling. Recrystallization of 6.4 g. of desired compoundfrom isopropanol (30 ml.) gave screening sample (5.4 g., M.P. 185l87).

Thin layer chromatography-solvent: CHCl 3A ethanol, 5; detector:phosphomolybdic acid.

Analysis.Calcd for C H N S (M.W. 142.23) (percent): C, 50.66; H, 7.09;N, 19.70. Found (percent): C, 50.43; H, 6.95; N, 19.48.

EXAMPLE 10 1- (4-fluorophenyl -5-methyl-2- (dimethylaminoethylmercaptoimidazole A solution of dimethylaminoethyl chloride (5.4 g., 0.05 mole)in anhydrous methanol (20 ml.) was added dropwise to a refluxingsuspension of 1-(4-fluoropheny1)- 5-methyl-Z-mercaptoimidazole (6.24 g.,0.03 mole) in anhydrous methanol (40 ml.). After addition was complete,the mixture was heated under reflux for 2 hours. The mixture was cooledand insoluble material (1.8 g., M.P. 350") was removed by filtration.The mother liquor was evaporated to dryness; the residue (10 g.) wassuspended in Water (10 ml.), the pH was adjusted to 9 with saturatedsodium carbonate solution and the mixture was extracted with chloroform.The resulting semi-solid (7 g.) was suspended in isopropanol (20 ml.);solid (starting material, 1.0 g.) was filtered off. The mother liquorwas evaporated to dryness and the residue was distilled under reducedpressure; first fraction, 0 .6 g., B.P. 131/0.08, 11 1.5611; secondfraction, 4.4 g., 13.1. 131-135/0.08, 11 1.5617. The two fractions wererecombinded, dissolved in isopropanol (reagent grade, 10 ml.) andethanolic hydrochloric acid (9.5 N, 11 ml.) was added. The solution wasevaporated to dryness and the residue was crystallized from isopropanol(15 ml.) to give salt (6.0 g., M.P. 173177 dec., hygroscopic). The saltwas redissolved in water 10 ml.), the solution was adjusted to pH 9 withsaturated sodium carbonate solution and extracted with chloroform (4X50ml.). The chloroform solution was dried over sodium sulfate, evaporatedto dryness and the residue was distilled under reduced pressure to yieldscreening sample (2.85 g., M.P. 121-126/0.05 mm., 11 1.5608).

' Analysis.Calcd for C H N SF (M.W. 279.37) (percent): C, 60.19; H,6.49; N, 15.04; S, 11.48. Found (percent): C, 60.16; H, 6.58;N, 14.91;S, 11.70.

heated under reflux with stirring for 2 hours. The mixture was cooledand insoluble material (1.5 g., M.P. 300) was removed by filtration. Themother liquor was evaporated to dryness and the residue was distilledunder reduced pressure to yield oil (5.4 g., B.P. 108-112") (0.07 mm.,12 1.5185). While cooling, ethanolic hydrochloric acid (9.5 N, 6 ml.)was added and the resulting solution was evaporated to dryness. Slowcrystallization occurred from isopropanol, isopropyl ether (1: 1, 20ml.); yield 5.2 g., M.P. 116-120 dec., hygroscopic. Above salt (6 g.)was dissolved in water (10 ml.) pH was adjusted to 9 with saturatedsodium carbonate solution and solution was extracted with chloroform.The resulting oil was distilled under high vacuum to yield screeningsample (2.6 g., B.P. 104105/0.05 mm., 11 1.5168).

Analysis.Calcd for C H N S (M.W. 241.39) (percent): C, 59.70; H, 9.60;N, 17.41; S, 13.28. Found (percent): C, 59.85; H, 9.86; N, 17.20; S,13.18.

Ultraviolet spectrum:

A252 224 mu, 253 mu EXAMPLE 12 1- (4-fluorophenyl -2-mercaptoimidazolep-Fluorophenyl isothiocyanate (12.24 g., 0.08 mole) was added to acooled solution of aminoacetaldehyde diethyl acetal (10.64 g., 0.08mole) in isopropanol (64 ml.). The mixture was heated under reflux forone-half hour. The mixture was cooled, conc. hydrochloric acid (6.4 ml.)was added and the mixture was again heated under reflux for 2 additionalhours. Crystallization occurred on cooling, yield, 9.0 g., M.P.205-207". A total of 9.8 g. of crude product was treated with charcoalin methanol (200 ml.). The methanol solution was re-evaporated todryness and the residue was twice recrystallized from ethanol (75 ml.)to give screening sample (6.9 g., M.P. 205207).

Analysis.Calcd for C H N SF (M.W. 194.23) (percent): C, 55.65; H, 3.63;N, 14.42; S, 16.51. Found (percent): C, 55.98; H, 3.76; N, 14.20; S,16.62.

Ultraviolet spectrum:

AMcOH max.

w-Aminoacetophenone hydrochloride (10.32 g., 0.06 mole) was added to acooled solution of methyl isothiocyanate (4.38 g., 0.06 mole) inisopropanol (reagent grade, 60 ml.); sodium bicarbonate (5.04 g., 0.06mole) was then added. The mixture was first stirred at room temperaturefor one hour and was then heated under reflux for three hours.Isopropanol was removed under reduced pressure and the residue wasdissolved in a mixture of water (25 ml.) and chloroform (50 ml.). Thechloroform layer was separated and the aqueous solution was furtherextracted with chloroform (3 50 ml.). The combined chloroform extractwas washed with water, dried over sodium sulfate and evaporated todryness. The colored residue (6.0 g.) was dissolved in methanol (200ml.); the solution was twice treated with charcoal and reevaporated todryness. The residue was recrystallized from isopropanol (50 ml.) threetimes to give screening sample (4.5 g., M.P. 178-180).

Analysis.Calcd for C H N S (M.W. 190.27) (percent): C, 63.12; H, 5.30;N, 14.73; S, 16.85. Found (percent): C, 63.35; H, 5.47; N,14.60; S,16.87.

Ultraviolet spectrum:

) A\IEOH max.

EXAMPLE 14 1-cyclohexy1-5methyI-Z-mercaptoimidazole Ultravioletspectrum:

Me OH mux.

EXAMPLE 15 1-(3-fluorophenyl)-S-methyl-Z-mercaptoimidazole3-fluoropheny1 isothiocyanate (6.12 g., 0.04 mole) was added to a cooledsolution of 1-amino-2,2-ethylenedioxypropane (4.68 g., 0.04 mole) inisopropanol (reagent grade, 32 ml.). The mixture was heated under refluxfor one-half hour; this was cooled, conc. hydrochloric acid 3.2 ml. wasadded and heating under reflux was continued for an additional hour.Product (7.8 g., M.P. 229231) crystallized on cooling. Recrystallizationfrom methanol (reagent grade, ml.) gave screening sample (6.7 g., M.P.227-229).

Analysis.--Calcd for C H N SF (M.W. 208.26) (percent): C, 57.66; I-I,4.35; N, 13.45; S, 15.40. Found (percent): C, 57.60; H, 4.43; N, 13.23;S, 15.12.

Ultraviolet spectrum:

EXAMPLE 16 1-(4-fluorophenyl)-5-phenyI-Z-mercaptoimidazolep-Fluorophenyl isothiocyanate (7.65 g., 0.05 mole) was dissolved inisopropanol (reagent grade, 50 ml.). The solution was cooled,w-aminoacetophenone hydrochloride (8.6 g., 0.05 mole) and sodium acetate(anhydrous, 4.1 g., 0.05 mole) were added. The mixture was heated underreflux for 5 hours. Isopropanol was removed by distillation underreduced pressure and the residue was suspended in water (50 ml.) andheated to boiling. The suspension was cooled, the precipitate wasfiltered oif, first washed with water (20 ml.) and then with isopropanol(50 ml.); yield, 7.95 g., M.P. 286-288 dec. Above product (10.3 g.) wasrecrystallized from ethanol (2500 ml.) to give screening sample (8.1 g.,M.P. 290 dec.).

Thin layer chromatography 90 CHCI 3A ethanol.

Analysis.-Calcd for C H FNaS (M.W. 270.33) (percent): C, 66.64; H, 4.10;N, 10.36; S, 11.86. Found (percent): C, 66.92; H, 4.39; N, 10.41; S,11.74. Ultraviolet spectrum:

EXAMPLE 17 l-(4-fluorophenyl)-5-methyl-2-imidazolemercaptoacetic acid1-(4-fluorophenyl)-S-methyl-Z-mercaptoimidazole (7.3 g., 0.035 mole) wassuspended in 5% aqueous sodium hydroxide solution. Chloroacetic acid(3.85 g., 0.0385 mole) was added and the mixture was stirred at roomtemperature overnight (18 hours). The resulting solution was acidifiedto pH 1 2 with cone. hydrochloric acid and extracted with chloroform (7X200 ml.). The crude product (7.5 g.) was recrystallized three times frombenzene ml.) to give screening sample (5.0 g., M.P. 164- 166). Thinlayer chromatography 50 acetic acid, 50 water.

Analysis.-Calcd for C H FN O S (M.W. 266.30) (percent): C, 54.12; H,4.17; N, 10.52. Found: (percent): C, 53.86; H, 4.07; N, 10.52.

Ultraviolet spectrum:

EXAMPLE 18 l-cyclopropylmethyl-S -methyl-2-mercaptoimidazole (a)Cyclopropylmethyl isothiocyanate.-A solution of amionmethylcyclopropanehydrochloride (19.4 g., 0.18

mole) in water (50 ml.) was added dropwise to a mixture of thiophosgene(20.7 g., 0.18 mole), calcium carbonate (50 g.), water (50 ml.) andchloroform (75 ml.) maintained at and agitated with vibromixer. Afteraddition was complete, the reaction mixture was agitated at 35-40 forthree hours. The reaction mixture was filtered to remove salts, thechloroform layer was removed and aqueous layer was extracted withchloroform (3x 200 ml.). The combined chloroform extract was washedfirst with hydrochloric acid and then water, dried over sodium sulfateand evaporated to small volume. Product (15.8 g., B.P. 70-7l/8 mm.) wasdistilled.

Analysis.Calcd (percent): N, 12.37; S, 28.33. Found (percent): N, 12.43;S, 28.53.

(b) Desired compound.--A mixture of cyclopropylmethyl isothiocyanate(9.04 g., 0.08 mole), 1-amino-2,2- ethylenedioxypropane (9.36 g., 0.08mole) in isopropanol (56 ml.) was heated under reflux for one-half hour.The reaction mixture was cooled, hydrochloric acid (conc. 5.6 ml.) wasadded and the mixture was again heated under reflux for one-half hour.Crystallization oc curred on cooling; yield: 6.4 g., M.P. 153-155. Thiswas dissolved in methanol, the methanolic solution was treated withcharcoal and evaporated to dryness. Two recrystallizations from ethylacetate (100 ml.) gave screening sample (4.7 g., M.P. 174-176). Ondrying at 60 and 0.1 mm. Hg melting point changes to 154-156.

Analysis.Calcd for C H N S (M.W. 168.27) (percent): C, 57.10; H, 7.19;N, 16.65; S, 19.05. Found (percent): C, 56.91; H, 7.11; N, 16.31; S,19.07.

EXAMPLE 19 1- 3-trifluoromethylphenyl) -5-methyl- Z-mercaptoimidazole(a) 3-trifluoromethylphenyl isothiocyanate.A solution ofm-aminobenzotrifluoride (34.9 g., 0.22 mole) in chloroform (50 ml.) wasadded dropwise to a mixture of thiophosgene (25.0 g., 0.217 mole),calcium carbonate (30 g.), water (70 ml.) and chloroform (70 ml.)maintained below in an ice-salt bath and agitated by means of avibromixer. After addition was complete, the mixture was agitated at35-40 for 3 hours. The reaction was then cooled, the salts were filteredoff, the chloroform layer was separated and the aqueous portion wasfurther extracted with chloroform (3x 200 ml.). The combined chloroformextract was washed first with 5% hydrochloric acid, then with water,dried over sodium sulfate and evaporated to small volume. Product (30.6g., B.P. 88-92") 8 mm. was distilled.

Analysis.Calcd (percent): N, 6.89; S, 15.78. Found (percent): N, 6.98;S, 16.27.

(b) Desired compound.A mixture of 3-trifluoromethylphenyl isothiocyanate(12.18 g., 0.06 mole), 1- amino-2,2-ethylenedioxypropane (7.02 g., 0.06mole) and isopropanol (48 ml.) was heated under reflux for onehalf hour.Hydrochloric acid (conc., 4.8 ml.) was added and the mixture was againheated under reflux for one hour. Product (10.6 g., M.P. 197-199)crystallized. Two recrystallizations from isopropanol (75 ml.) yieldedscreening sample (7.8 g., M.P. 196-198").

Analysis.-Calcd for C H N F S (M.W. 258.28) (percent): C, 51.15; H,3.52; N, 10.85; S, 12.41. Found (percent): C, 51.22; H, 3.56; N, 10.70;S, 12.27.

Ultraviolet spectrum:

A122 257 mu (6, 10,500) EXAMPLE 20 1- 3 -trifluoromethylphenyl)-2-mercaptoirnidazole A solution of aminoacetaldehyde diethylacetal(7.98 g., 0.06 mole) in 25 ml. of isopropanol was added slowly to acooled solution of 3-trifluoromethylphenyl isothiocyanate (12.18 g.,0.06 mole) in isopropanol (25 ml.). The reaction mixture was then heatedunder reflux for one-half hour and cooled. Hydrochloric acid (conc., 4.8

ml.) was added and heating under reflux was continued for two hours.Product (4.7 g., M.P. 155-156) crystallized on cooling; second crop: 2.8g., M.P. 155-157. Recrystallization from isopropanol (20 ml., charcoal)gave screening sample (4.2 g., M.P. 155-158).

Thin layer chromatography: CHCl 5 3A EtOH.

Analysis.-Calcd for C H F N S (M.W. 244.24) (percent): C, 49.18; H,2.89; N, 11.47; S, 13.13. Found (percent): C, 49.44; H, 3.04; N, 11.42;S, 13.43.

Ultraviolet spectrum: x )245 my 6, 9,300),- 279 M 292 1* (a A solutionof fi-phenethyl isothiocyanate (8.15 g., 0.05 mole) in isopropanol (20ml.) was cooled in a 3-neck flask. l-amino-2,2-ethylenedioxypropane(5.85 g., 0.05 mole) and additional isopropanol (20 ml.) was added. Thereaction mixture was stirred under reflux for onehalf hour, and cooled.Hydrochloric acid (conc., 4 ml.) was added and heating under reflux wascontinued for one hour. Product (8.2 g., M.P. 151-154) crystallized oncooling. Recrystallization from ethyl acetate (50 ml.) gave yellowproduct (7.3 g., M.P. 154-156); a methanol solution (200 ml.) wastreated with charcoal and reevaporated to dryness. Two furtherrecrystallizations from ethyl acetate yielded product (6.1 g., M.P.153-155"). One further recrystallization from isopropanol (15 ml.) gavescreening sample (4.35 g., M.P. 152154).

Thin layer chromatography: 95 CHCl,, 5 3A EtOH.

Analysis.Calcd for C H N S (M.W. 218.31) (percent): C, 66.02; H, 6.46;N, 12.83; S, 14.69. Found (percent): C, 66.22; H, 6.39; N, 13.00; S,14.67.

Ultraviolet spectrum:

MeOH mnx.

Propyl isothiocyanate (8.08 g., 0.08 mole) was added to a cooledsolution of 1-amino-2,2-ethylenedioxypropane (9.36 g., 0.08 mole) inisopropanol (64 ml.). The mixture was heated under reflux for one-halfhour; this was cooled, hydrochloric acid (conc., 6.4 ml.) was added, andheating under reflux was continued for an additional one-half hour.Product 7.6 g., M.P. -165 crystallized on cooling. Recrystallizationfrom ethyl acetate (75 ml.) gave yellow crystals (6.3 g., M.P. 162-165 Amethanolic solution of the above was treated with charcoal andreevaporated to dryness. One further recrystallization from ethylacetate and two recrystallizations from isopropanol (15 ml.) gavescreening sample (3.3 g., M.P. 162164).

Thin layer chromatography: 95 CHCl 5 3A EtOH.

Analysis.-Calcd for C H N S (M.W. 156.26) (percent): C, 53.81; H, 7.74;N, 17.92; S, 20.53. Found (percent): C, 54.04; H, 7.87; N, 17.63; S,20.53.

Ultraviolet spectrum:

M OH Mix.

EXAMPLE 23 1-phenyl-2-mercaptoimidazole 1 1 Thin layer chromatography:95 CHCl 5 3A ethanol. Analysis.-Calcd for C H N S (M.W. 176.24)(percent): C, 61.33; H, 4.58; N, 15.90; S, 18.19. Found (percent): C,61.34; H, 4.75; N, 15.90; S, 17.97.

Ultraviolet spectrum:

H52 219 my (6, 11,000), 279 my. (6, 7,500)

EXAMPLE 24 1- (fl-diethylarninoethyl) -5-methyl-Z-mercaptoimidazolehydrochloride (a) Diethylarninoethyl isothiocyanate.A solution ofdiethylaminoethylamine (25.17 g., 0.217 mole) in chloroform (50 ml.) waadded dropwise to a mixture of thiophosgene (25.0 g., 0.217 mole),calcium carbonate (30.0 g.), water (70 ml.) and chloroform (70 ml.)maintained at less than in an ice bath and agitated thoroughly withvibrornixer. After the addition was complete, the reaction mixture wasagitated at -40 for three hours. The reaction mixture was filtered toremove salts, the chloroform layer was removed, the aqueous layer wasrendered alkaline to pH 9 with saturated sodium carbonate solution andextracted with chloroform (3x200 ml.). The chloroform extracts werecombined, washed with water, dried over sodium sulfate and evaporated toa small volume under low vacuum. Product (12.1 g., B.P. 102-103/8 mm., n1.5039) was distilled.

(b) Desired compound.-A solution of 1-amino-2,2- ethylenedioxypropane(5.85 g., 0.05 mole) in isopropanol (20 ml.) was added to a cooledsolution of diethylarninoethyl isothiocyanate (7.90 g., 0.05 mole) in 20ml. isopropanol. The reaction mixture was heated under reflux forone-half hour. The recation mixture was again cooled in an ice bath,ethanolic hydrochloric acid (9.9 N, 10 ml.) was added and the reactionmixture stirred under reflux for one hour. Product (8.8 g., M.P.184-186") crystallized on cooling. Two recrystallizations fromisopropanol (150 ml., charcoal treatment) yielded screening sample (6.3g., M.P. 186-188). Cf. E. Schmidt et al., Ann. 612,11 (1957).

Thin layer chromatography: dioxane, C H 5 EtOH, 5 NH OH, faintimpurities were detected.

Analysis.--Calcd for CmHg ClNgS (percent): C, 48.07;H, 8.07; N, 16.82;Cl, 14.19; S, 12.84. Found (percent): C, 47.90; H, 8.21; N, 16.62; Cl,14.09; S, 12.91.

Ultraviolet spectrum:

MeOH Mm.

(a) 3-phthalimido-2-butanone.A mixture of potassium phthalimide (105.7g., 0.57 mole), 3-bromo-2-butanone (90.6 g., 0.6 mole) and anhydrousbenzene ml.) was stirred under reflux for 5 hours. The reaction mixturewas filtered hot and the salts were thoroughly washed with boilingbenzene. The benzene solution was evaporated to dryness, and the residuewas recrystallized from isopropanol (35 ml.) to yield desired product(756 g., M.P. 81- 83). Recrystallization from isopropanol gaveanalytical sample (M.P. 82-84). Cf. Gabriel, B. 46, 1346.

Analysis.Calcd for C H NO (percent): C, 66.35; H, 5.10; N, 6.45. Found(percent): C, 6.47; H, 5.12; N, 6.54.

Ultraviolet spectrum:

k 295 my, 249 my, 220 my for four hours. The solution was cooled, wasWashed first with saturated sodium bicarbonate solution (75 ml.), thenwith water, dried over sodium sulfate and evaporated to dryness. Theresidual oil was distilled under high vacuum to yield oil (61.0 g., B.P.126-128/0.033 mm. Hg n 1.5485) which solidifies on cooling.Redistillation gave analytical sample (B.P. 146-147/ 0.1 mm. Hg, 111.5510, M.P. 59-62).

Analysis.Calcd for C H NO (percent): C, 64.63; H, 5.74; N, 5.22. Found(percent): C, 64.36; H, 5.79; N, 5.36.

(c) 3,3-ethylenedioxy 2 butylamine.A mixture of3-phthalimido-2,2-ethylenedioxybutane (51.0 g., 0.195 mole) and 25% KOHsolution (200 mls.) was heated under reflux with stirring for two andone-half days. The alkaline solution was extracted with methylenechloride (4 200 ml.). The methylene chloride extract was dried oversodium sulfate and distilled under Water vacuum. Product (12.85 g., B.P.60-61/11 mm. Hg, 12 1.4431) distilled.

Analysis.-Calcd for C H NO (percent): C, 54.94; 'H, 9.99; N, 10.68.Found (percent): C, 54.84; H, 10.19; N, 10.71.

(d) Desired compound.-p-Fluorophenyl isothiocyanate (7.65 g., 0.05 mole)was added to a cold solution of 3,3-ethylenedioxy-2 butylarnine (6.55g., 0.05 mole) in isopropanol (40 ml.). The reaction mixture was heatedunder refiux with stirring for one half hour. The reaction mixture wascooled in an ice bath. Hydrochloric acid (cone, 4.0 ml.) was added andthe reaction mixture was heated under reflux with stirring for threehours. Product (9.6 g., M.P. 259-61) crystallized on cooling. Tworecrystallizations from ethanol ml.) yielded screening sample (6.1 g.,M.P. 260-3).

Ultraviolet spectrum:

l\r[c0E EXAMPLE 26 1- (Z-pyridyl -S-methyI-Z-mercaptoimidazole (a)Pyridine-2-isothiocyanate.-Pyridine 2 isothiocyanate was prepared aspreviously described by A. E. S. Fairfield and D. A. Peak, J. Chem. Soc.1955, 796.

(b) Desired compound.-1-amino 2,2 ethylenedioxy propane (7.02 g., 0.06mole) in isopropanol (24 ml.) was added slowly to a cooled solution ofpyridine-Z-isothiocyanate (8.16 g.) in isopropanol (24 ml.). The mixturewas heated under reflux for /2 hour and cooled in an ice bath. EthanolicHydrochloric acid (12 ml., 9.9 N) was added and the reaction mixture wasstirred under reflux for one hour. Product (9.8 g., M.P. 206-8)crystallized. The product (the hydrochloride salt) was suspended inwater (30 ml.), the pH was adjusted to 9 with saturated sodium carbonatesolution and the suspension was extracted with chloroform (3X60 ml.).The chloroform extract was washed with water, dried over sodium sulfateand evaporated to dryness to give solid (7.8 g., M.P. -7"). The freebase was treated with charcoal in methanol solution (100 ml.), themethanolic solution was re-evaporated to dryness, and the product wastwice recrystallized from isopropanol (60 ml.) to yield screening sample(4.4 g., M.P. 185-7).

Ultraviolet spectrum:

l\vI2H 255 H1M e 11,700)

13 EXAMPLE 27 1-benzyl-5-methyl-2-mercaptoimidazole Ultravioletspectrum:

AAJEOH Thin layer chromatography: 90 CHCl 10 3A ethanol.

Analysis.Calcd for C H N S (M.W. 204.30) (percent): C, 64.66; H, 5.92;N, 13.71; S, 15.70. Found (percent): C, 64.54; H, 6.07; N, 13.43; S,15.72.

EXAMPLE 28 1-(4-chlorophenyl)-2-mercaptoimidazole (a) Aminoacetaldehydediethylacetal isothiocyanate.- A solution of aminoacetaldehydediethylacetal (27.0 g., 0.2 mole) in chloroform (50 ml.) was addeddropwise to a mixture of thiophosgene (25.0 g., 0.217 mole), calciumcarbonate (30.0 g.), water (70 ml.), and chloroform (20 ml.), maintainedat less than 10 by means of an ice-salt bath and agitated thoroughlywith vibromixer. After the addition was complete the reaction mixturewas agitated at 3540 for three hours. The reaction mixture was filteredto remove salts, the chloroform layer was removed, the aqueous layer wasrendered alkaline to pH 8-9 with saturated sodium carbonate solution andextracted with chloroform (3 x200 ml.). The chloroform extracts werecombined, washed with water, dried over sulfate and evaporated to smallvolume under low vacuum. Product (30.7, B.P. 10ll03/10 mml.) wasdistilled. (Cf. Easson, A. P. T and Pyman, F. L., J. Chem. Soc. 1932,1806).

(b) Desired compound-A solution of aminoacetaldehyde diethylacetalisothiocyanate (10.0 g., 0.0575 mole) in isopropanol (25 ml.) was addeddropwise to an icecooled solution of p-chloroaniline (7.36 g., 0.0575mole) in isopropanol (25 ml.). The mixture was then heated under refluxfor one-half hour and cooled. Hydrochloric acid (come. 48 ml.) was addedand heating under reflux was resumed for three hours. Product (8.7 g.,M.P. 222- 224) crystallized on cooling, was dissolved in hot methanol;the methanolic solution was treated with charcoal and re-evaporated todryness. Two recrystallizations of the residue from isopropanol (150ml.) gave screening sample (5.33 g., M.P. 222-224").

Thin layer chromatography: 90 CHCl 10 3A EtOH.

Analysis.Calcd for C H ClN S (M.W. 210.69) (percent): C, 51,31; H, 3.34;N, 13.30; S, 15.22; Cl, 16.83. Found (percent): C, 51.51; H, 3.28; N,13.31; S, 15.23; Cl, 16.94. Ultraviolet spectrum:

xgfgg 222 m). (5, 21,000) 289 m (6, 6,600)

EXAMPLE 29' 1-(3,4-dichlorophenyl)-2-mercaptoimidazole A solution ofaminoacetaldehyde diethylacetal isothiocyanate (10.0 g., 0.0575 mole) inisopropanol (25 ml.) was added dropwise to an ice-cooled solution of3,4-dichloroaniline (9.3 g., 0.0575 mole) in isopropanol (25 ml.). Themixture was then heated under reflux for onehalf hour and cooled.Hydrochloric acid (conc., 4.8 ml.) was added and heating under refluxwas resumed for three hours. Product (12.9 g., M.P. 241243 dec.)crystallized. This was recrystallized from methanol (charcoal, 400 ml.)to yield white product (7.1 g., M.P. 241- 244). Further recrystalizationfrom ethanol (ca. 150 ml.) gave screening sample (6.2 g., M.P. 239-242dec.). Thin layer chromatography: CHCl 10 3A EtOH. Analysis.Calcd for CH CI N S (M.W. 245.13) (percent): C, 44.10; H, 2.47; N, 11.43; S, 13.08;Cl, 28.93. Found (percent): C, 44.37; H, 2.49; N, 11.70; S, 13.23; Cl,29.19. Ultraviolet spectrum:

M532 226 my (6, 19,000); 298 In (6, 5,000)

EXAMPLE 30 1- (4-methoxyphenyl) -2-mercaptoimidazole A solution ofaminoacetaldehyde diethyl acetal isothiocyanate (10.0 g., 0.0575 mole)in isopropanol (25 ml.) was added dropwise to an ice-cooled solution ofp-anisidine (7.12 g., 0.0575 mole) in isopropanol (25 ml.). The mixturewas then heated under reflux for one-half hour and cooled. Hydrochloricacid (conc. 4.8 ml.) was added and heating under reflux was continuedfor three additional hours. Product (5.7 g., M.P. 2142l6) crystallized.Two recrystallizations from ethanol ml.) gave screening sample (4.45 g.,M.P. 215218 dec.).

Thin layer chromatography: 90 CHCl 10 3A EtOH.

Analysis.Calcd for C H N SO (M.W. 206.27) (percent): C, 58.22; H, 4.89;N, 13.58; S, 15.55. Found (percent): C, 58.47; H, 4.98; N, 13.88; S,15.55. Ultraviolet spectrum:

N55? 230 m (6, 13,500); 272 m (6, 8,000)

EXAMPLE 31 1- (3 -pyridyl) -2-merc aptoimidazole A solution ofaminoacetaldehyde diethylacetal isothiocyanate (14.0 g., 0.08 mole) inisopropanol (30 ml.) was slowly added to a cooled solution of3-arninopyridine (7.52 g., 0.08 mole) in isopropanol (35 ml.). Thereaction mixture was heated under reflux for one-half hour and cooled inan ice bath. Ethanolic hydrochloric acid (9.9 N, 16 ml.) was added.Heating under reflux was resumed for three hours. The product (14.8 g.,M.P. 271-273") crystallized as the hydrochloride salt. This wasdissolved in water (ca. 75 ml.), the solution was neutralized to pH 8with saturated sodium carbonate solution yielding a tan precipitate(11.3 g., M.P. 247250 dec.). This was recrystallized from methanol(charcoal, 250 ml.) to give product (9.2 g., M.P. 249251 dec.). Twoadditional recrystallizations from methanol (200 ml.) gave screeningsample (7.5 g., M.P. 248-250 dec.).

Thin layer chromatography: 90 CHCl 10 3A EtOH.

Analysis.Calcd for CgHqNgS (M.W. 177.23) (percent): C, 54.21; H, 3.98;N, 23.71; S, 18.09. Found (percent): C, 54.31; H, 4.26; N, 23.53; S,18.05. Ultraviolet spectrum:

MeOH M...

A solution of aminoacetaldehyde diethylacetal isothiocyanate (10.50 g.,0.06 mole) in isopropanol (25 ml.) was added solwly to an ice-cooledsolution of 2,3-dimethylaniline (7.26 g., 0.06 mole) in isopropanol (25ml.). The mixture was then heated under reflux for onehalf hour andcooled. Hydrochloric acid (conc. 4.8 ml.) was added and heating underreflux was resumed for 18 hours. Product (8.4 g., M.P. 265268 dec.)crystallized. Recrystallization from isopropanol (charcoal, 800 ml.)yielded colorless product (7.62 g., M.P. 262-266 dec.). Furtherrecrystallization from isopropanol (ca. 500 ml.) yielded screeningsample (6.8 g., M.P. 265-268 dec.).

Thin layer chromatography: 90 CHCl 10 3A EtOH.

Analysis.Calcd for C H N S (M.W. 204.30) (percent): 0, 64.68; H, 5.92;N, 13.70; s, 15.70. Found M on rmin.

EXAMPLE 33 1- (2,4-difluorophenyl) -2-mercaptoirnidazole A solution ofaminoacetaldehyde diethylacetal isothiocyanate (12.25 g., 0.07 mole) inisopropanol (30 ml.) was added slowly to an ice cooled solution of2,4-difiuoroaniline (9.03 g., 0.07 mole) in isopropanol (30 ml.). Themixture was then heated under refluxed for onehalf hour and cooled.Hydrochloric acid (conc., 5.6 ml.) was added and heating under refluxwas continued for 3 hours. Product (11.2 g., M.P. 209-212") crystallizedon cooling. Two recrystallizations from ethanol (150 ml.) gave screeningsample (4.1 g./M.P. 212-214"); low recovery due to accidental loss.

Thin layer chromatography: 90 CHC1 10 3A EtOH.

Analysis.Calcd for C H N SF (M.W. 212.23) (percent): C, 50.93; H, 2.85;N, 13.20; S, 15.13. Found (percent): C, 51.03; H, 3.08; N, 13.47; S,15.32. Ultraviolet spectrum:

max.

A solution of aminoacetaldehyde diethylacetal isothiocyanate (12.25 g.,0.07 mole) in isopropanol (30 ml.) was added slowly to an ice cooledsolution of p-aminobenzotrifluoride (11.27 g., 0.07 mole) in isopropanol(35 ml.). The mixture was then heated under reflux for one-half hour andcooled. Hydrochloric acid (cone. 4.8 ml.) was added, and heating underreflux was continued for three additional hours. Product (8.98 -g., M.P.194197) crystallized on cooling. Recrystallization first from isopropylether (charcoal, 600 m1.) and then from benzene (100 m1.) yieldedscreening sample (5.7 g., M.P. 196- 198").

Thin layer chromatography: 90 CHCl -10 3A EtOH.

Analysis.Calcd for C10H7F3N2S (M.W. 244.25) (percent): C, 49.17; H,2.89; N, 11.47; S, 13.13. Found (percent): C, 49.42; H, 3.03; N, 11.29;S, 13.39. Ultraviolet spectrum:

igzg 24.5 mu (6, 11,100), 304 m (5, 4,500)

EXAMPLE 35 1- 3-fluorophenyl) -2-mercaptoimidazole A solution ofaminoacetaldehyde diethyl acetal (10.64 g., 0.08 mole) in isopropanol(30 ml.) was slowly added to an ice-cooled solution of 3-fluorophenylisothiocyanate (12.24 g., 0.08 mole) in isopropanol (30 ml); the mixturewas then heated under reflux for one-half hour and cooled. Hydrochloricacid (conc., 6.4 ml.) was added and heating under reflux was resumed forone hour. Product (9.4 g., 158-160) crystallized on cooling. Tworecrystallizations from isopropanol (ca. 25 1111.) gave screening sample(7.5 g., M.P. 159 162").

Thin layer chromatography: 95 CHC1 5 3A EtOH.

Analysis.-Calcd for C H FN S (M.W. 194.23) (percent): C, 55.65; H, 3.63;N, 14.43; S, 16.51). Found (percent): C, 55.75; H, 3.62; N, 14.22; S,16.80. Ultraviolet spectrum:

max.

EXAMPLE 36 1 2,6-dimethylphenyl) -2-mercaptoimid-azole mixture was thenheated under reflux for one-half hour and cooled. Hydrochloric acid(conc. 6.4 ml.) was added and heating under reflux was continued foreight hours. Product (11.3 g., M.P. 308 dec.) crystallized. Tworecrystallizations from ethanol (400 ml.) yielded screening sample (7.8g., M.P. 30l306 dec.).

Thin layer chromatography: 90 CHCI 10 3A EtOH.

Analysis.Calcd for C H N S (M.W. 204.30) (percent): C, 64.68; H, 5.92;N, 13.70; S, 15.70. Found (percent): C, 64.60; H, 5.95; N, 13.82; S,15.51. Ultraviolet spectrum:

EXAMPLE 37 1- (Z-fiuorophenyl) -2-mercaptoimid azole A solution ofaminoacetaldehyde diethylacetal isothiocyanate (15.75 g., 0.09 mole) inisopropanol (35 ml.) was slowly added to an ice-cooled solution ofo-fluoroaniline (9.99 g., 0.09 mole) in isopropanol (35 ml.). Thesolution was then heated under reflux for one-half hour and cooled.Hydrochloric acid (conc., 7.2 ml.) was added, and heating under refluxwas continued for three hours. Product (12.3 g.) crystallized oncooling. Recrystallization from ethanol (charcoal), followed byrecrystallization from isopropanol ml.) yielded screening sample (8.5g., M.P. 187-190).

Thin layer chromatography: CHC1 10 3A EtOH.

Analysis.--Calcd for C H FN S (M.W. 194.24) (percent): C, 55.65; H,3.64; N, 14.42; S, 16.51). Found (percent): C, 55.79; H, 3.71; N, 14.64;S, 16.72. Ultraviolet spectrum:

xztgg 250 m5 (6, 9,300

EXAMPLE 3:;

1- 2-chloro-5-trifluoro methylphenyl) -2- mercaptoimidazole A solutionof aminoacetaldehyde diethylacetal isothiocyanate (14.0 g., 0.08 mole)in isopropanol (30 ml.) was added slowly to a solution ofQ-chlorod-trifluoromethylaniline (15.68 g., 0.08 mole) in isopropanol(35 ml.) precooled in an ice bath. The mixture was then heated underreflux for one-half hour and cooled. Hydrochloric acid (conc., 6.4 ml.)was added, and heating under reflux was continued for eight hours.Product (13.5 g., M.P. 202-205") crystallized. Recrystallization firstfrom benzene (ca. 500 ml.) and then from ethyl acetate ml.) yieldedscreening sample (8.1 g., M.P. 204-206").

Thin layer chromatography: 90 CHCl 10 3A EtOH.

Analysis.Calcd for C H ClF N S (M.W. 278.70) (percent): C, 43.09; H,2.18; AN, 10.05; S, 11.50; Cl, 12.72. Found (percent): C, 43.28; H,2.10; N, 10.22; S, 11.82; Cl, 12.62. Ultraviolet spectrum:

M. OH Mi...

1- 2,6-dichlorop-heny-l -2-mercaptoimidazole A solution ofaminoacetaldehyde diethylacetal isothiocyanate (10.50 g., 0.06 mole) inisopropanol 30 ml.) was slowly added to an ice-cooled solution of2,6-dichloroaniline (9.60 g., 0.06 mole) in isopropanol (25 ml.). Themixture was then heated under reflux for one-half hour and cooled.Hydrochloric acid (conc., 4. 8 ml.) was added, and heating under refluxwas continued for 18 hours. Product (12.8 g., M.P. 300-305 dec.)crystallized. Two recrystallizations from methanol (400 ml.) yieldedscreening sample (8.4 g., M.P. 302-305 dec.).

Thin layer chromatography. 90 CHC1 10 3A EtOH.

Analysis.Calcd for C H Cl N S (M.W. 245.14) (percent): C, 44.10; H,2.47; N, 11.43; S, 13.07; Cl, 28.93.

17 Found (percent): C, 44.03; H, 2.45; N, 11.72; S, 13.1-3; Cl, 28.84.Ultraviolet spectrum:

1 .1552 263 rm (6, 13,800) EXAMPLE 40 1- 4-bromophenyl)-2-mercaptoimidazole A solution of aminoacetaldehyde diethylacetalisothiocyanate (12.25 g., 0.07 mole) in isopropanol (30 ml.) was addedslowly to an ice-cooled solution of p-bromoaniline (12.0 g., 0.07 mole)in isopropanol (30 ml.). The reaction mixture was heated under refluxfor one-half hour and cooled. Hydrochloric acid (conc. 5.6 ml.) wasadded and heating under reflux was continued for three hours. Product(14.86 g., M.P. 244249 dec.) crystallized. Two recrystallizations fromethanol (charcoal, 1000 ml.) yielded screening sample (11.2 g., M.P.244-248).

Thin layer chromatography: 90 CHCl 10 3A EtOH.

Analysis.-Calcd for CgHqBI'NgS (M.W. 255.16) (percent): C, 42.35; H,2.77; N, 10.99; S, 12.53; Br, 31.31. Found (percent): C, 42.65; H, 2.80;N, 11.22; S, 12.52; Br, 31.32. Ultraviolet spectrum:

1X52 290 m (6, 6,400) 226 mu (6, 21,600)

EXAMPLE 41 1-(4-fluoro-2-methylphenyl)-2-mercaptoimidazole A solution ofaminoacetaldehyde diethylacetal isothiocyanate (10.50 g., 0.06 mole) inisopropanol (25 ml.) was added to an ice-cooled solution of4-fluoro-2-methylaniline (7.5 g., 0.06 mole) in isopropanol (25 ml.).The resulting solution was heated under reflux for one-half hour, andcooled. Hydrochloric acid (conc. 5 ml.) was added and the mixture washeated under reflux for eight additional hours. Product (7.6 g., M.P.211-215 crystallized on cooling. Two recrystallizations from isopropanol(200 ml., charcoal) yielded screening sample (5.4 g., M.P. 216-218).

Thin layer chromatography: 90 CHCl 3A EtOH.

Analysis.Calcd for C H FN S (M.W. 208.26) (percent): C, 57.67; H, 4.36;N, 13.45; S, 15.40. Found (percent): C, 57.82; H, 4.42; N, 13.73; S,15.46.

EXAMPLE 42 1-(4-iodophenyl)-2-mercaptoimidazole A solution ofaminoacetaldehyde diethylacetal isothiocyanate (8.75 g., 0.05 mole) inisopropanol ml.) was added to an ice-cooled suspension of p-iodoaniline(10.95 g., 0.05 mole) in isopropanol (20 ml.). The resulting reactionmixture was heated under reflux for one-half hour and cooled.Hydrochloric acid (conc. 4.0 ml.) was added and heating under reflux wascontinued for three hours. Product (11.2 g., M.P. 245-248 dec.)crystallized. Three recrystallizations from ethanol (250 ml., charcoal)yielded screening sample (7.20 g., M.P. 249-251" dec.).

Thin layer chromatography: 90 CHCl 10 3A EtOH.

Analysis.-Calcd for C H IN S (M.W. 302.15) (percent): C, 35.77; H, 2.33;N, 10.28. Found (percent): C, 35.97; H, 2.32; N, 10.07. Ultravioletspectrum:

x1552 237 m 6, 26,600); 201 m (6, 6,500)

EXAMPLE 43 1-(4-fluorophenyl)-4-methyl-2-ethylmercaptoimidazolehydrochloride (a) a-Aminopropionaldehydediethylacetal.u-Arninopropioualdehyde diethylacetal was prepared fromoz-bl'O- mopropionacetal as described by R. Burtles et al., J. Chem.Soc. 1925, 581.

(b) Desired compound.-A mixture of ot-aminopropionaldehyde diethylacetal(11.76 g., 0.08 mole), p-fiuorophenyl isothiocyanate (12.24 g., 0.08mole) in anhydrous benzene (80 ml.) was heated under reflux for one-halfhour. The solution was evaporated to dryness;

hydrochloric acid (6 N, ml.) was added and the mixture was heated underreflux for 17 hours. Product corresponding to1-(p-fluorophenyl)-4-methy1-2-mercaptoimidazole (0.7 g., M.P. 212-213")crystallized on cooling. The mother liquor was extracted with chloroform(3 75 ml.); the chloroform extract was evaporated to dryness and theresidue was crystallized from ethylacetate (50 ml.) to give titlecompound (16.2 g., M.P. 159161 dec.). A portion of this hydrochloridesalt (9.0 g.) was dissolved in water, the solution was rendered basic topH 9 with saturated sodium carbonate solution and extracted withchloroform to give oil (7.4 g.). This was redissolved in isopropanol(reagent grade, 10 ml.), ethanolic hydrochloric acid (9.9 N, 3.5 ml.)was added, and title compound (6.4 g., M.P. 160-162 dec.) crystallized.Recrystallization from isopropanol (10 ml.) gave screening sample (4.8g., M.P. 159151 dec.).

Thin layer chromatography: CHCl 5 3A EtOH.

Analysis.Calcd for C H CIFN S (M.W. 272.78) (percent): C, 52.83; H,51.7; N, 10.27; S, 11.76; Cl, 13.00. Found (percent): C, 53.06; H, 5.34;N, 10.28. S, 11.90; Cl, 13.01. Ultraviolet spectrum:

EXAMPLE 44 1-(3-pyridyl)-5-methyl-2-mercaptoirnidazole (a) 3-pyridineisothiocyanate.3-pyridine isothiocyanate was prepared by a methoddiffering from that previously described by A. E. S. Fairfull, D. A.Peak, J. Chem. Soc. 1955, 796. Thiophosgene (25.0 g., 0.217 mole) wasadded dropwise while cooling to a mixture of 3- aminopyridine (20.42 g.,0.217 mole), CaCO (50.0 g.), chloroform ml.) and water (100 ml.)agitated by means of a vibromixer. After the addition was complete thereaction mixture was agitated at 35-40 for three hours. Salts wereremoved by filtration, the chloroform layer was separated and theaqueous layer was further extracted with chloroform (3 X200 ml.). Thechloroform extract was washed with water, dried over sodium sulfate andevaporated to dryness. The residue was then distilled to yield titlecompound (2.4 g., B.P. 108109/9 mm.).

(b) Desired compound.--1-amino-2,2-ethylene dioxypropane (1.17 g., 0.01mole) in isopropanol (4 ml.) was added dropwise to a cooled solution of3-pyridine isothiocyanate in isopropanol (4 ml.). The reaction mixturewas heated under reflux for one-half hour and cooled. Ethanolichydrochloric acid (9.9 N, 2.0 ml.) was added and the reaction mixturewas again stirred under reflux for one hour. Product (2.2 g., M.P.269-271 dec.) crystallized on cooling. This hydrochloride salt wasdissolved in water (10 ml.), the solution was rendered alkaline to pH 89with saturated sodium carbonate solution and the precipitated solid wasremoved by filtration; yield: 1.6 g., M.P. 227229. Recrystallizationfrom isopropanol (50 ml.) gave screening sample (1.4 g., M.P. 225-227).

Analysis.Calcd for C H N S (M.W. 191.25) (percent): C, 56.51; H, 4.75;N, 21.96; S, 16.77. Found (percent): C, 56.61; H, 4.76; N, 21.88; S,16.80. Ultraviolet spectrum:

EXAMPLE 45 5- 3 ,4-dichlorophenyl) -1-mcthyl-2-mcrcaptoimidazole (a)3,4-dichloro-a-isonitroacetophenone.Butyl nitrite (0.1 mole, 10.31 g.)was added dropwise over period of one hour to a solution of3,4-dichloroacetophenone (0.1 mole, 1 8.9 g.) in anhydrous ether whileanhydrous HCl was slowly bubbled through the solution at roomtemperature. HClgas addition was continued for 15 minutes after additionof butyl nitrite was complete. Exothermic reaction suddenly occurred andthe reaction mixture was stirred at room temperature for 6 /2 hours. Thereaction mixture was evaporated to dryness under reduced pressure, theresidue was suspended in benzene (50 ml), the suspension was stored inrefrigerator overnight and filtered; yield: 10.8 g., M.P. l3943.

(b) (It-Amino 3,4 dichloroacetophenone hydrochloride.A suspension of3,4-dichloro-wisonitrosoacetophenone (28.7 g., 0.13 mole) in a mixtureof ethanol 2B (750 ml.) and concentrated hydrochloric acid (13.0 ml.)was bydrogenated at room temperature and atmospheric pressure in thepresence of platinum on charcoal (5%, 3.0 g.). Theoretical quantity ofhydrogen was consumed in 15 minutes after which time hydrogen uptakeceased completely. The reaction mixture was filtered; the residue(crystallized product and catalyst) was dissolved in a mixture ofboiling methanol-water and the hot solution filtered to remove catalyst.The combined ethanol, methanol and water solution was evaporated todryness under reduced pressure at 50, the residue was crystallized frombenzene to give the desired product (29.0 g., M.P. 255-7 (0) 3,4dichlorophenyl-1-methyl-5,2mercaptoimidazole.uAmino-3,4-dichloroacetophenone hydrochloride (0.10 mole, 22.4 g.) wasadded to a solution of methyl isothiocyanate (0.1 mole, 7.13 g.) inanhydrous pyridine (150 ml.). The reaction mixture was stirred at 80 for18 hours, cooled and poured into ice Water (ca. 600 ml.). Oily residueformed which crystallized on standing. This was collected, heated with 3N NaOH (500 ml.); the hot solution Was filtered hot to remove insolublematerial, diluted with water (500 ml.), cooled and repeatedly washedwith ether. The resulting solution was acidified with cone. HCl whilecooling, the resulting solid was removed by filtration and washed withwater; yield: 12.7 g., M.P.- 180-95". Recrystallization first from ethylacetate (ca. 200 ml., charcoal G-60), then from isopropanol (ca. 150ml.) gave light tan product (8.1 g., M.P. 197-200). Tworecrystallizations from benzene (spectro reagent grade, 100 ml.,charcoal G-60) gave the desired product (6.3 g., M.P. 197-201").

Analysis.Calcd for C H Cl N S (M.W. 259.17) (percent): C, 46.34; H,3.11; N, 10.81; S, 12.37; Cl, 27.36. Found (percent): C, 46.62; H, 3.14;N, 10.98; S, 12.33; Cl, 27.07.

EXAMPLE 46 l-phenyl-S- (p-chlorophenyl)-2-mercaptoimidazolea-Amino-p-chloroacetophenone hydrochloride (0.042 mole, 9.17 g.) wasadded to a cold solution of phenylisothiocyanate (0.042 mole, 5.67 g.)in pyridine (dry, 70 ml.). The mixture was stirred at room temperaturefor an hour and at 80 for fifteen hours. The solution was then pouredinto ice water (125 ml.) and the suspension was made basic with Na CO(satd. solution). The suspension was stirred for an hour at roomtemperature and the product was filtered 01f and washed well with Waterand then isopropanol. Beige crystals (11.13 g., M.P. 293-7") wereobtained. The crude material was recrystallized from DMSO (125 ml.) andisopropanol (300 ml.) to give cream colored crystals (9.40 g., M.P.300-2). A second recrystallization from DMSO (95 ml.) and isopropanol(325 ml.) yielded 8.50 g. of the desired product; M.P. 303-6.

Analysis.-Calcd for C H ClN S (M.W. 286.78) (percent): C, 62.83; H,3.86; N, 9.77; S, 11.18. Found (percent): C, 62.55; H, 3.83; N, 9.79; C,11.29.

EXAMPLE 47 l-(2-pyridyl)-5- (p-chlorophenyl)-2-mercaptoimidazole (a)1-(2-pyridyl) 3 (p-chlorophenacyl)-2-thiourea.--a-Amino-p-chloroacetophenone hydrochloride (0.06 mole, 12.4 g.) wasadded to a cold solution of Z-pyridine isothiocyanate (.06 mole, 8.25g.) in dry pyridine (100 ml.). The mixture was stirred at roomtemperature for an hour and then at 80 for 15 hours. The mixture waspoured into ice water (180 ml.) after cooling to room temperature andthe solution was made basic with Na CO (satd. soln.,

' 225 ml.). The crude product was filtered off and washed The productprecipitated out of the reaction mixture upon cooling. It was filteredoff, washed with methanol, and dried in the vacuum oven; Yield: 6.33 g.,M.P. 283-7". The crude product was recrystallized from methanol (abs.reag., 300 ml.) to yield pure product sample (4.63 g., M.P. 283-7").

Ultraviolet spectrum:

N352 300 mu Analysis.Calcd for C H ClN S (M.W. 287.77) (percent): C,58.43; H, 3.51; N, 14.61;Cl, 12.33; S, 11.15. Found (percent): C, 58.14;H, 3.77; N, 14.53; Cl, 12.41; S, 11.14.

As indicated above, the compounds described hereinabove can be employedas anti-inflammatory agents to treat the four cardinal symptoms ofinflammation: swelling, redness, pain and heat. The anti-inflammatory,analgesic and anti-pyretic effects in warm-blooded animals weredetermined by carrageenin, UV erythema, grid shock, hot box andanti-pyretic tests as follows (1a) Anti-inflammatory: Carrageeuin TestMale rats, five per group, Weighing between 150-200 g., were given thetest compounds orally one hour before carrageenin. 0.1 cc. ofcarrageenin was injected into the plantar area of the right hind paw.Three hours after administration of carrageenin and four hours afteradministration of test compounds or vehicle, the rats were sacrificed.Right and left hind paws were removed and weighed. The differencebetween these paws was determined for all animals within a group and theaverage difference calculated. The average difierence of the vehiclecontrol group was used as a point of comparison for test groups. If theaverage difference for a test group was smaller than that of the vehiclecontrol, protection is present and is expressed in percentage of vehiclecontrol. The following illustrative results were obtained.

TABLE I Dose Percent Z-mercaptoimrdazoleS (mg/kg.) Protection1-methyl-5-(3-ehlorophenyl)- 52 50 40 25 40 12. 5 28 1,5-dimethyl- 10048 50 13 l-ethyl-5-methyl- 100 29 l-11-butyl-5-methyl- 100 27l-allyl-5-methyl- 100 37 l-cyclopropylmethy methy 100 43l-cyclohexyl-S-rnethyl- 100 54 1- (4-fiuorophenyl)-5-methyl- 100 49 1-(3-fluorophenyl) -5-methyl- 100 37 1- (3-trlfiuoromethylphenyl)-5-methyl100 34 l-phenyl- 100 37 1- (3, 4-diehlorophenyl)- 100 14 1-l-fluorophenyl) 100 41 1-methyl-5-phenyl-. 100 42 l-n-propyl-5-rnethyl100 37 1- (4-fluorophenyl)-4,5 at 100 26 1- (2-pyridyl)-5-methyl- 100 261- (3-pyn'dyl)- 100 7 With l-butyl 5methyl-2-(carboethoxymercapto)imidazole andl-(4-fluorophenyl)-5-methyl-2-imidaZole-mercaptoacetic acid the percentprotection obtained at 100 mg./kg. is 21.

(b) Anti-inflammatory: Ultra Violet Erythema Test Guinea pigs, eithersex, five per group, weighing between 275-375 grams, having their hairremoved by using animal electrical clippers followed by chemicaldepilation with Nair. The next morning test compounds are give norally.Half of the total dose is given one hour before ultra violetirradiation. The other half is given immedately after U.V. exposure.Erythema is produced by 60 second exposure to ultra violet rays emittedby a Hanovia Analytical Model Quartz Lamp with a 500 watt high pressuremercury burner. In order to localize erythema to three 7 mm. areas,guinea pigs are confined in rubber gloves with three 7 mm. holes cut inthem. Evaluation of results takes place 2 hours and 24 hours after ultraviolet exposure. Erythema spots are scored from O to 3 giving a maximumtotal of 9 for an unprotected animal.

=No visible signs of erythema 1=Faint trace of erythema 2=Definite butill defined area of erythema 3=Definite and clearly defined area oferythema The scores of all animals within a given group are addedtogether. A maximum score for any group of animals is 45 and is calledthe Maximum Degree of Inflammation. Any group with a degree ofinflammation greater than vehicle control has 0% protection. Groups withvalues less than the control groups have protection and this isexpressed in percent. Table II shows illustrative results.

TAB L E II Dose Percent 2-mercaptoimldazoles (mg. /kg;) Protection1,5-dimethyl- 100 85 50 42 25 51 1-n-butyl-5-metl1yl- 100 68l-allyl-fi-methyL. 25 53 l-( i-fiuorophenyl) 50 40 l-rnethyl-S-pheuy 10078 l-eyclohexyl-S-methyl 50 28 1- (Ii-fluorophenyl) --methyl- 100 55 l-(3-trifluoromethylphenyl)- 100 26 l-cyclopropylmethyl-S-methyl-. 50 4 1-(3-tn'fluoromethylphenyl)- 100 44 l-n-propyl-fi-methyl- 100 87 l-phenyl-100 86 l-(-fluorophenyl) -4,5-diInethyl- 75 60 1- (2 pyridyl)-5-methyl-100 61 l-benzyl5-methyl-. 100 24 l- (4-methoxyphenyl)- 100 311-(3-pyridyl)- 100 36 1-(2, difluorophenyl) 100 67 1- (3-fluorophenyl)-100 74 1- (2-fiuorophenyl)- 100 53 1- (4-iod0phenyl)- 100 48 1,4-dirnethyl-5-phenyl 100 57 -phenyl-5-methyl- 100 54l-methyl-S-(4-n1ethoxyphenyl)- 108 5 25 42 1-methyl-5-(3-chlorophenyl)-100 76 1-methy1-5-(4-fiuorophenyl)- 100 831,4dimethyl-5-(l-methoxyphenyl)- 100 61 1 ,4-dimethyl-5-(4-fluorophenyl)- 100 36 1-methyl-5-(4-chlorophenyl)- 100 43 l-methyl-5(3-trifluoromethylphenyl) 100 64 5-(4-ehlorophenyl)- 100 40 5-(3,4-dichlorophenyl)-1-methyl- 100 60 22 With1-(4-fluorophenyl)4-methyl-2-ethylmercaptoimadazole HCl the percentprotection obtained at rug/kg. is 21.

(2a) Analgesic Activity: Grid Shock Test Five male Charles River mice,weighing 17-22 g. were used per group. Control readings were takenbefore oral administration and first test readings were taken 30 minutesafter oral administration. Subsequent readings were taken at 30 minuteintervals. Compounds to be administered orally were suspended in 3 cornstarch solution. Concentrations varied but the maximum volume for p.o.administration was 0.44 cc. The mice were placed, individually, on awire grid permitting freedom of movement, and exposed to a fairlyconstant and rapid increase in voltage. The point at which a mouse feelspain is determined on an oscilloscope by the distortion of a square wavecaused by the mouse making and breaking contact on the grid. The averageof two readings was taken at each time interval, on each mouse, andpercent changes were calculated within each group. The followingillustrative results were obtained.

(b) Analgesic Activity: Hot Box Test The mice are placed on copperplates at room temperature. The plates are heated by a hot plate. Painthreshold is reached when the hind limbs exhibit a sequence of rapidwithdrawal reflexes. Male Charles River mice weighing 18-30 g., four pergroup, are used. The mice are fasted for 4 hours; two control readingsare taken 30 minutes apart. Following oral administration, readings aretaken at 30, 60, 90 minutes or more depending on the activity andduration of the compounds. Table IV gives illustrative results.

TABLE IV Percent Dose Pro- 2-mercaptounidazoles (mg. lkg.) tection 1,5-dimethyl 80 32 1-n-butyl-5-methyl- 80 29 1 (4-flu0r0phenyD-5-methy 8032 1-ethyl-5-methyl- 80 14 40 37 20 18 1- (4-fiuorophenyl)-. 80 201-methyl-5-phenyl- 80 24 40 26 20 20 1-(3-trifluoromethylphenyl)- Z8l-eyclopropylmethyl-5-methy1- 50 14 1-n-propyl-5-methyl- 80 22 l-phen 8015 1- (4fluorophenyl)-4- 5-dimethyl- 80 23 40 18 20 18 l- (2,4-difiuorophenyl)- 80 20 1- (3-fiuorophenyl)- 80 15 l-(4-iodophenyl)-.80 26 With 1-(4-methoxyphenyl)-5-methyl-2 methylmercaptoimidazole,1-(4-fluorophenyl) S methyl 2 (dimethylamino-ethylmercapto)imidazole,1-(4-fluoropheny1) 5- methyI-Z-imidazolemercapto acetic acid and1-(4-fluorophenyl)-4-methyl-2-ethylmercaptoimidazole HCl the percentprotection obtained respectively, at 80, 5'0, 80 and 50 mg./kg. is 24,17, 55 and 18.

(3) Anti-pyretic Screen Male rates, :5 g., were injected s.c. in thenape of the neck with 15% suspension of Brewers Yeast Powder(Mead-Johnson) at rate of 1 cc./100 g. body weight. Sixteen to eighteenhours later rectal temperatures were taken. Rats were rearranged to givefour rats per group and to have relatively uniform temperatures. Testcompounds were given orally in 2% gum acacia and one group received onlythe vehicle. One hour after the test material was given, rectaltemperatures were again taken and continued at hourly intervals for 3hours. The difference in temperature before drug administration and eachhour after drug administration was calculated. The average of thesetemperature changes was used to compare test compounds with the vehiclecontrol and standard (antipyrin). The following results were obtained.

TABLE V Avg. Temp.

Dose Change Z-mercaptoimidazoles (mg/kg.) F.

1, 5-dirnethyl- 100 3. 9 l-ethyl-frmethylu 100 3. 3 l-n-butyl-5-methyl-100 3. 8 1-allyl-5-methyl- 100 5. 9 1- (4-fluorophenyl)-5-methyl- 12(1))g 1(4-1'lu0ro phenyD-E-methyl- 100 -4. 8 1-rnethy1-5-phenyl- 100 --3. 6l-phen l- 100 2. 6 l-n-propyl-S-methyL. 100 5. 3 l-phen 100 2. 6

(4) Toxicity Studies (48 hour) Toxicities were determined on the basisof gross symptoms seen over a wide dose range of test compounds in CPmice. The vehicle was 3% corn starch. Five mice were used with each doselevel. The route of administration was peroral. Results were as follows:

l-(4-fiuorophenyl-4,S-dimethyl)- 1250 2/ 6 deaths.

More specifically, 1-(4-fluorophenyl)-2-mercaptoimidazole had thefollowing LD s in various animals:

Mouse540 mg./kg. i.p.

Mouse-60 mg./ kg. p.o.

Rat-ca: 700 mg./ kg. p.o.

Rabbit-over 500 mgJkg. p.o. Dogover 300 mg./kg. p.o.

Monkey (Saimiri)-o ver 300 mg. kg. p.o.

The anti-inflammatory agents of this invention can be administered byany of the conventional means available for use in conjunction withpharmaceuticals. Pharmaceutical composition in dosage unit form compriseabout mg. to about 500 mg. of the active ingredients.

To produce dosage units for peroral application, the active substancesof general formula 1 or a salt thereof is combined, e.g. with solidpowdered carriers such as lactose, sucrose, sorbitol, mannitol; starchessuch as potato starch, corn starch or amylopectin, also laminaria powderor citrus pulp powder; cellulose derivatives or gelatin, also lubricantssuch as magnesium or calcium stearate of polyethylene glycols(carbowaxes) of suitable molecular weights may be added, to formcompressed tablets or core tablets for sugar coating. The latter arecoated, for example, with concentrated sugar solutions which e.g. cancontain gum arabic, talcum and/or titanium dioxide, or they are coatedwith a lacquer dissolved in easily volatile organic solvents or mixtureof organic solvents. Dyestuffs can be added to these coatings, forexample, to distinguish between different contents of active substance.Soft gelatin captules (pearl-shaped closed capsules) and other capsulesconsist for example of a mixture of gelatin and glycerin and contain,e.g., mixtures of the active substance or a suitable salt thereof withCarbowax and hard gelatin capsules contain, for example, granulates ofthe active substance or a suitable salt thereof with solid, powderedcarriers such as, e.g. lactose, sucrose, sorbital, mannitol; starchessuch as potato starch, corn starch or amylopectin, cellulose derivativesor gelatin, as well as magnesium stearate or stearic acid. Suppositoriesare employed as dosage units for rectal application. These consist of acombination of the active substance or a suitable salt thereof with aneutral fatty base, or also gelatin rectal capsules can be employedwhich consist of a combination of the active substance of a suitablesalt thereof with polyethylene glycols (carbowaxes) of suitablemolecular weight.

Ampoules for parenteral, particularly intramuscular administrationpreferably contain a water soluble salt of the active substance ofFormula 1 and suitable stabilizing agents and, if necessary, buffersubstances in aqueous solution. Anti-oxidizing agents such as sodiumbisulfite, sodium sulfite, ascorbic acid or -Rongalit(formaldehydesodium bisulfite compound) are suitable as stabilizingagents either alone or combined, in total concentrations between about0.01 and about 0.5 percent. Because of its ability to form chelates,ascorbic acid has an addi tional stabilizing effect; in this function itcan also be replaced by other chelate-formers. The best stability of theactive ingredient is attained, e.g. by mixtures in suitable ratio ofsodium sulfite, sodium bisulfite and/or ascorbic acid, or by theaddition of other bufier substances such as citric acid and/or saltsthereof. In addition, the ampules can contain a slight amount of a usualpreservative.

Useful pharmaceutical formulations for administration of the compoundsof this invention may be illustrated as follows:

CAPSULES Mg. Active ingredient l0-500 Lactose 20-100 Corn starch, U.S.P.20l00 Aeroso ized silica gel 24 Magnesium stearate 1-2 TABLETS Mg.Active ingredient 100 Microcrystalline cellulose 50 Corn starch, U.S.P.Lactose, U.S.P. 50 Magnesium stearate, U.S.P. 2

This tablet can also be sugar coated according to the usual artpractices. Colors may be added to the coating.

CHEWABLE TABLETS Mg. Active ingredient Mannitol, N.F. 100 Flavor 1Magnesium stearate, U.S.P. 2

SUPPOSITORIES Mg. Active ingredient 100 Suppository base 1900Polyethylene glycol 6001.0 cc. Sodium bisulfite, U.S.P.-0.4 mg. Waterfor injection, U.S.P. (q.s.)2.0 cc.

According to the above disclosure, the invention apart from thepyridyl-substituted Z-mercaptoimidazole derivatives which can beconsidered as a separate aspect of this invention, then pertains toZ-mercaptoimidazole derivatives of the formula R is lower alkyl; loweralkenyl; cycloalkyl; cycloalkyllower-alkyl; monocarbocyclic aryl;monocarbocyclic aryl lower alkyl; di-lower-alkylamino-lower-alkyl; loweralkoXy-lower alkyl;

R is hydrogen, di-lower-alkylamino-lower-alkyl, carbolower-alkoxy orlower alkylcarboxy,

R is hydrogen or lower alkyl, and

R is lower alkyl or monocarbocyclic aryl, provided that R is lower alkylonly when R; is monocarbocyclic aryl; and provided further that R, islower alkyl only when R is a group other than lower alkyl.

26 What is claimed is: 1. A compound of the formula I SR5 wherein R islower alkyl; or phenylmono-substituted by lower alkyl, lower alkoxy,halogen or trifluoromethyl; R is hydrogen,di-loWer-alkylamino-lower-alkyl, R is hydrogen or lower alkyl, and R islower alkyl or phenyl monosubstituted by lower alkyl, lower alkoxy,halogen or trifluoromethyl, provided that R is lower alkyl only when R;is said monosubstituted phenyl.

2. 1-(4-flu0rophenyl)-5-methyl-2-mercaptoimidazole. 3. 1(3-trifluoromethylphenyl)-5-methyl-2-mercaptoimidazole.

4. 1-cyclopropylmethyl-5-methyl-2-mercaptoimidazole. 5. 1(4-fluorophenyl)-4,S-dimethyl-Z-mercaptoimidazole.

6. 1methyl-5-phenyl-2-mercaptoimidazole.

References Cited UNITED STATES PATENTS 2/1952 Jones 260'309 OTHERREFERENCES Dakin et al., Chem. Abst. vol. 22, p. 3882 (1928).

Dodson et al., Chem. Abst. vol. 44, column 6415 (1950).

Gabriel Berichte, vol. 41, pp. 1926-8 (1908).

Hildesheimer, Chem. Abst. vol. 5, pp. 486-7 (1911).

Jones et al., 1 our. Amer. Chem. Soc. vol. 71, pp. 4000 2 (1949).

NORMA S. MILESTONE, Primary Examiner NATALIE TROUSOF, Assistant ExaminerUS. Cl. X.R.

Column Column Column Column Column Column Column Column Column ColumnColumn Column Column Column Patent No.

Inventor(s) Ka UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 2line 28 2 line 41 2 line 3 line A line 69 8 line 8 line line line

line

DatedAJmil 7, 1970 It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

"econitic" should read aconitic (5%) of material; M.P. 2o3-205 shouldread g. were then added, the mixture heated to reflux and a C14H NaO S"Uultraviolet" should read Ultraviolet "acid" should be omitted.

"C H FNaS" should read C H FN S "amionmethylcyclopropane" should readaminomethylcyclopropane "c 6A7," should read c 66.47,

"/10 mml. should read /lO mm.

"refluxed" should read reflux "AN, 10.05; should read N, 10.05;

"cyanate (10.50 g., 0.06 mole) in isopropanol ml. should read cyanate(10.50 g. 5 0.0 mole) in isopropanol (30 ml.)

"H, 51.7" should read H, 5.17

"give norally' should read given orally FORM PO-OHO-69) USCOMM-DC 60376469 \r us, sovmuuun ram-rims nrrlcl: nu o-Ju-au UNITED STATES PATENTOFFICE CERTIFICATE OF CORRECTION Pat n 5.505.550 Dated Anril 7. 1970Inventofls) Karl J. Doebel and Andre R. Gagneux PAGE 2 It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 23 line 44 "350 4/6 deaths" should read 250 4/6 deaths Column 24line 15 'sorbital" should read sorbitol Signed and sealed this 11th dayof April 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents FORM PO-1D50 0-69)

